2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists

ABSTRACT

Novel 2-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 2-substituted piperidine analogs as selectively active antagonists of N-methyl-D-aspartatc (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, convulsions, amioglycoside antibiotics-induced hearing loss, migraine headaches, chronic pain, glaucoma, CMV retinitis, psychosis, urinary incontinence, opioid tolerance or withdrawal, or neurodegenerative disorders, such as lathyrism, Alzheimer&#39;s Disease, Parkinsonism and Huntington&#39;s Disease are described.

This application is 371 of PCT/W96/20767 filed Dec. 20, 1996 whichclaimed priority benefit of provisional application Ser. No. 60/009,182filed Dec. 22, 1995.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is related to 2-substituted piperidine analogs. Theanalogs are selectively active as antagonists of N-methyl-D-aspartate(NMDA) receptor subtypes. The invention is also directed to the use of2-substituted piperidine analogs as neuroprotective agents for treatingconditions such as stroke, cerebral ischemia, central nervous systemtrauma, hypoglycemia, anxiety, convulsions, aminoglycosideantibiotics-induced hearing loss, migraine headaches, chronic pain,glaucoma, CMV retinitis, psychosis, urinary incontinence, opioidtolerance or withdrawal, or neuro-degenerative disorders such aslathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.

2. Related Background Art

Excessive excitation by neurotransmitters can cause the degeneration anddeath of neurons. It is believed that this degeneration is in partmediated by the excitotoxic actions of the excitatory amino acids (EAA)glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor.This excitotoxic action is considered responsible for the loss ofneurons in cerebrovascular disorders such as cerebral ischemia orcerebral infarction resulting from a range of conditions, such asthromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia,cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such asfrom drowning, pulmonary surgery and cerebral trauma, as well aslathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease.

Various classes of substituted piperidine analogs are known. Forexample, U.S. Pat. No. 5,036,077 generically discloses piperidinederivatives described by the formula: ##STR1## wherein Ar represents aphenyl group substituted by R₂, R₃ and R₄ or a naphth-1-yl ornaphth-2-yl group, substituted or unsubstituted by 1 or 2 halogen atoms;X represents an oxygen atom or sulfur atom; R₁ represents H or a halogenatom; R₂ represents a halogen atom, a trifluoromethyl group, a phenylgroup which is unsubstituted or substituted by 1 to 3 halogen atoms, aphenoxy group which is unsubstituted or substituted by 1 to 3 halogenatoms, or a C₁ -C₄ alkyl group and the benzyl group substitutes thepiperidine radical in the 2, 3 or 4 position. This reference does notexemplify 2-substituted piperidines. The piperidines are said to beuseful as antimicrobial agents, but there is no disclosure or suggestionof treating disorders responsive to selective NMDA receptor subtypeantagonists.

Canadian Patent No. 696,999 is directed toN-(alkylene)aryl-2-substituted piperidines useful as vasodilators whichare described by the formula: ##STR2## wherein A is an alkylene grouphaving 2 to 3 carbon atoms. There is no mention of using the compoundsof this reference as NMDA receptor antagonists or treating disordersresponsive thereto.

PCT International Publication Number WO 93/15052 generically describescompounds that are said to be calcium channel antagonists represented bythe formula: ##STR3## and the salts thereof, wherein R is C₁₋₈alkyl(phenyl)p, C₂₋₈ alkenyl(phenyl)p, C₂₋₈ alkynyl(phenyl)p, C₃₋₈cycloalkyl or C₁₋₈ alkyl C₃₋₈ cycloalkyl;

p is 0 to 2;

n is 0 to 6;

m is 0 to 6;

A is a bond, --CH═CH--, --C.tbd.C--, oxygen, sulphur or NR¹ ;

R¹ is hydrogen, C₁₋₈ alkyl or phenyl C₁₋₄ alkyl; and

Ar is aryl or heteroaryl, each of which may be optionally substituted.2-[2-(3,4-Dichlorophenoxy)ethyl]-1-cinnamylpiperidine oxalatehemihydrate and 4-[2-(2-Dibenzofuranyloxy)ethyl]-1-cinnamylpiperidineoxalate are exemplified. The compounds of this reference are said to beuseful for treating anoxia, ischaemia, such as stroke, migraine,epilepsy, traumatic head injury, AIDS-related dementia,neurodegenerative diseases and drug addiction withdrawal. This referencedoes not disclose or suggest NMDA receptor activity, let alone selectiveNMDA receptor subtype antagonism.

European Patent Application No. 235,463 generically discloses calciumantagonists represented by the formula ##STR4## wherein; p is zero, oneor two; ##STR5## m is zero to six inclusive; ##STR6## d and n areselected from zero or one and the dotted lines represent double bondswhich may form consistent with the valence of carbon;

Ar, D and R are selected from the group consisting of ##STR7## and inaddition, R may have the values: ##STR8## cycloalkyl or loweralkyl, andD may have additionally the values: ##STR9## Ar (CH₂)₁₋₄, X, Y and Z areselected from the group consisting of hydrogen, lower alkyl, halogen,##STR10## z is one or zero with the proviso that z cannot be zero at thesame time n is zero when one of the following occurs at the same timethat D is phenyl or substituted phenyl: (A)_(d) is hydrogen, (A)_(d) iscyano, (A)_(d) is aminocarbonyl, or a double bond forms between the αcarbon and a carbon of the central heterocyclic amine-ring; R¹ isselected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R² isselected from loweralkyl, phenyl and phenylloweralkyl; M is apharmaceutically acceptable metal ion and the pharmaceuticallyacceptable salts thereof, including acid addition salts, quaternarysalts, and hydrates and alcoholates thereof. This reference disclosesthat such compounds may be useful as coronary vasodilators,antihypertensives, antiarrhythmic, antiallergy, antihistamic andantisecretory agents. No compounds substituted at the 2 position of thepiperidine ring are exemplified nor is there any disclosure orsuggestions of NMDA antagonistic activity.

U.S. Pat. No. 5,192,799 generically disclosed amines described by theformula: ##STR11## wherein R₃ -R₄ can be taken together to form 4- to8-membered ring and substituted by aryl, benzyl and heteroaryl. No2-benzylpiperidine was exemplified in this reference. The compounds aresaid to be useful for the treatment and prevention of heart diseases.But there is no disclosure or suggestion of treating disordersresponsive to selective NMDA receptor subtype antagonists.

European patent application No. 649838 generically disclosed cyclizedamines described by the formula: ##STR12## wherein the nitrogenheterocycles can be 3-8 member rings and substituted in the 2-4positions. Ar and Ar' are opt. mono or disubstituted phenyl. No.2-benzylpiperidine was exemplified in this reference. The compounds aresaid to be useful to treat arrhythmia and tachycardia. But there is nodisclosure or suggestion of treating disorders responsive to selectiveNMDA receptor subtype antagonists.

Japanese patent application No. 04217945 disclosed amines described bythe formula: ##STR13## wherein R₄ -R₅ can be taken together to form 5-to 8-membered ring and substituted by benzyl and phenyl. The compoundsare said to be useful as antiulcer agents. But there is no disclosure orsuggestion of treating disorders responsive to selective NMDA receptorsubtype antagonists.

U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidineether derivatives for use as antipsychotic agents selective for sigmareceptors. Similarly, PCT International Publication No. WO 92/18127 andPCT International Publication No. WO 91/06297 generically discloseN-phthalimidoalkyl piperidines which are useful as antipsychotic agentsand which are selective for sigma receptors. However, 2-substitutedpiperidines are not exemplified by any of these references and there isno mention of NMDA receptor activity.

Numerous references have disclosed piperidine derivatives substituted atthe 4 and 3 position for use in a variety of treatments. Such referencesinclude, for example, U.S. Pat. No. 3,255,196 (3 and 4-substitutedpiperidines that are active antitussives and possess analgesic,antiemetic and local anaesthetic properties); U.S. Pat. No. 5,202,346(4-substituted piperidines that are Class III antiarrhythmic agents);PCT International Publication No. WO 92/02502 (3 and 4-substitutedpiperidines which are calcium channel blockers expected to be useful inthe treatment of anoxia, ischemia including stroke, migraine, epilepsy,traumatic head injury, AIDS-related dementia, neurodegenerative diseasesand drug addiction); PCT International Publication No. WO 88/02365 (3and 4-substituted piperidines that may be useful for treatment of mentaldisorders accompanying cerebrovascular disease); BE 860701(4-substituted piperidines for use as vasodilators and β-adrenergicinhibitors); FR 2681319 (4-substituted piperidines for use asneuroprotectors and anticonvulsants); and DE 2939292 (4-substitutedpiperidines for use as antiallergenic and antiinflammatory agents). Noneof these references discloses or suggest 2-substituted piperidineanalogs or their use as selective NMDA receptor subtype antagonists.

Excitatory amino acid receptor antagonists that block NMDA receptors arerecognized for usefulness in the treatment of disorders. NMDA receptorsare intimately involved in the phenomenon of excitotoxicity, which maybe a critical determinant of outcome of several neurological disorders.Disorders known to be responsive to blockade of the NMDA receptorinclude acute cerebral ischemia (stroke or cerebral trauma, forexample), muscular spasm, convulsive disorders, neuropathic pain andanxiety, and may be a significant causal factor in chronicneurodegenerative disorders such as Parkinson's disease [T. Klockgether,L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiencyvirus (HIV) related neuronal injury, amyotrophic lateral sclerosis(ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D.M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington'sdisease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P.A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge,Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.].NMDA receptor antagonists may also be used to prevent tolerance toopiate analgesia or to help control withdrawal symptoms from addictivedrugs (Eur. Pat. Appl. 488,959A).

Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) inNakanishi's lab in 1991 provided an initial view of the molecularstructure of the NMDA receptor [Nature 354, 31-37 (1991)]. There areseveral other structurally related subunits (NMDAR2A through NMDAR2D)that join NR1 in heteromeric assemblies to form the functional ionchannel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108(1994)]. The molecular heterogeneity of NMDA receptors implies a futurepotential for agents with subtype selective pharmacology.

Many of the properties of native NMDA receptors are seen in recombinanthomomeric NR1 receptors. These properties are altered by the NR2subunits. Recombinant NMDA receptors expressed in Xenopus oocytes havebeen studied by voltage-clamp recording, as has developmental andregional expression of the mRNAs encoding NMDA receptor subunits.Electrophysiological assays were utilized to characterize the actions ofcompounds at NMDA receptors expressed in Xenopus oocytes. The compoundswere assayed at four subunit combinations of cloned rat NMDA receptors,corresponding to four putative NMDA receptor subtypes [Moriyoshi, et al.Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221;Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem.Biophys Res. Commun. 1992, 185, 826-832].

An object of this invention is to provide novel 2-substituted piperidineanalogs which function as subtype-selective NMDA receptor antagonists.

A further object of this invention is to provide a pharmaceuticalcomposition containing an effective amount of the 2-substitutedpiperidine analogs to treat cerebrovascular disorders responsive to theselective blockade of NMDA receptor subtypes.

Another object of this invention is to provide a method of treatingdisorders responsive to the subtype-selective NMDA receptor antagonistsin an animal by administering a pharmaceutically effective amount of2-substituted piperidine analogs.

SUMMARY OF THE INVENTION

This invention relates to novel 2-substituted piperidine analogsrepresented by the formula (I): ##STR14## or a pharmaceuticallyacceptable salt thereof wherein Ar¹ and Ar² are independently aryl or aheteroaryl group, either of which may be independently substituted byhydrogen, hydroxy, alkyl, a halogenated alkyl group, halogen, nitro,aryl, aralkyl, amino, a lower alkyl amino group or a lower alkoxy group;

each R¹ is independently hydrogen, alkyl or hydroxy;

each R² is independently hydrogen, alkyl or hydroxy;

X is --CH₂ --, O, S or NR³, wherein R³ is hydrogen or a lower alkylgroup having 1 to 6 carbon atoms;

Y is --CH₂ --, --CH═CH--, --C.tbd.C--, O, S or NR³ ;

m is 0, 1 or 2; and

n is 0, 1, 2, 3, 4 or 5,

provided that when m is 0 and X is --CH₂ --, or m is 1, R¹ is H and X is--CH₂ -- that either Y is not --CH₂ -- or at least one of R² is nothydrogen and further provided that when Y is --C═C-- then X is not O.

The compounds of the present invention may exist as optical isomers andthe inventive compounds include both the racemic mixtures of suchoptical isomers as well as the individual entantiomers.

Examples of pharmaceutically acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate,mandelate, oxalate, and the acetate. Alternatively, pharmaceuticallyacceptable inorganic and organic base addition salts may be used such assodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine,and bromine are preferred groups.

Alkyl means a straight or branched chain of from one to six carbon atomsor cyclic alkyl of from three to seven carbon atoms including, but notlimited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Aryl means a monocyclic or bicyclic carbocyclic aromatic ring systemwhich can be substituted or unsubstituted, for example, but not limitedto phenyl, naphthyl or the like.

Heteroaryl means a monocyclic or bicyclic carbocyclic aromatic ringsystem substituted by one or more hetero atoms, which can be the same ordifferent, and includes, for example, thienyl, benzo[b]thienyl, naphtho[2,3[b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxanthiinyl, 2H-pyrrolyl, pyrrolyl,imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl,quinozalinyl, cinnolinyl, pteridinyl, 5aH-carbozolyl, carbozolyl,β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl,phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl,phenoxazinyl groups, quinoxalinyl, 2,3-dioxoquinoxalinyl,benzimidazolyl, 2-oxobenzimdazolyl and 2-oxindolyl groups.

Aralkyl means any of the alkyl groups defined herein substituted by anyof the aryl groups as defined herein.

Halogenated alkyl means any of the alkyl groups defined hereinsubstituted by one or more of the halogen groups defined herein,including but not limited to a trifluoromethyl group.

Lower alkyl amino means any of the alkyl groups defined hereinsubstituted by an amino group.

Lower alkoxy means an alkoxy group containing an alkyl group as definedherein.

The instant invention is also related to a pharmaceutical compositioncontaining the compound defined by formula I in an amount effective totreat cerebrovascular disorders responsive to the selective blockade ofNMDA receptor subtypes and a pharmaceutically acceptable carrier.Exemplary disorders responsive to such treatment include cerebralischemia caused by cerebral trauma, stroke, hypoglycemia, heart attack,and surgery; anxiety; psychosis; schizophrenia; glaucoma; CMV retinitis,urinary incontinence; opioid tolerance of withdrawal; and chronicneurodegenerative disorders such as Huntington's disease, ALS,Parkinsonism and Alzheimer's disease. The pharmaceutical composition ofthis invention may also be employed as an analgesic or for the treatmentof epilepsy or migraine headaches.

The invention further relates to a method for treating disordersresponsive to the selective blockade of N-methyl-D-aspartate receptorsubtypes in an animal suffering thereof which comprises administering inunit dosage form at least one compound represented by the formula:##STR15## or a pharmaceutically acceptable salt thereof wherein Ar¹ andAr² are independently aryl or a heteroaryl group, either of which may beindependently-substituted by hydrogen, hydroxy, alkyl, a halogenatedalkyl group, halogen, nitro, aryl, aralkyl, amino, a lower alkyl aminogroup or a lower alkoxy group;

each R¹ is independently hydrogen, alkyl or hydroxy;

each R² is independently hydrogen, alkyl or hydroxy;

X is --CH₂ --, O, S or NR³, wherein R³ is hydrogen or a lower alkylgroup having 1 to 6 carbon atoms;

Y is --CH₂ --, --CH═CH--, --C.tbd.C--, O, S or NR³ ;

m is 0, 1 or 2; and

n is 0, 1, 2, 3, 4 or 5.

DETAILED DESCRIPTION OF THE INVENTION

The novel 2-substituted piperidine analogs of this invention arerepresented by previously defined formula (I).

Preferred embodiments of the novel 2-substituted piperidine analogs ofthis invention are represented by formulae (III-VI). In particular, oneembodiment is represented by formula (III) as follows: ##STR16## or apharmaceutically acceptable salt thereof wherein Ar¹ and Ar² areindependently aryl or a heteroaryl group, either of which may beindependently substituted by hydrogen, hydroxy, alkyl, a halogenatedalkyl group, halogen, nitro, aryl, aralkyl, amino, a lower alkyl aminogroup or a lower alkoxy group;

each R¹ is independently hydrogen, alkyl or hydroxy;

each R² is independently hydrogen, alkyl or hydroxy;

Q is --C═C-- or --C.tbd.C--;

Z is --CH₂ --, O, S or NR³ ;

m is 0, 1 or 2; and

n is 0, 1, 2, 3, 4 or 5, provided that when Q is --C═C-- then Z is notO.

Two additional embodiments of the novel 2-substituted piperidine analogsof this invention are represented by formulae (IV-V) as follows:##STR17## or a pharmaceutically acceptable salt thereof, or ##STR18## ora pharmaceutically acceptable salt thereof, wherein Ar¹, Ar², R¹, R², Z,m and n are the same as previously defined.

Yet another embodiment of the novel compounds of this invention isrepresented by the formula (VI): ##STR19## or a pharmaceuticallyacceptable salt thereof, wherein Ar¹, Ar², R¹, R², m and n are the sameas previously defined and L is --CH₂ --, O, S or NR³.

Exemplary preferred compounds of formula I include, without limitation:

*2-Benzyl-1-(2-phenoxy)ethylpiperidine;

*2-Benzyl-1-(2-(4-trifluoromethyl)phenoxy)ethylpiperidine;

**2-Benzyl-1-(2-(3-amino)phenoxy)ethylpiperidine

**2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenoxy)ethylpiperidine;

**2-Benzyl-1-(3-phenoxy)propylpiperidine;

*2-Benzyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine;

*2-(4-chlorophenyl)methyl-1-(3-(3-amino)phenoxy)propylpiperidine;

**2-Benzyl-1-(4-phenoxy)butylpiperidine;

*2-Benzyl-1-(4-(3-trifluoromethyl)phenoxy)butylpiperidine;

*2-Benzyl-1-(4-(3-amino)phenoxy)butylpiperidine;

2-Benzyl-1-(4-(2-trifluoromethy)phenoxy)butylpiperidine;

**2-Benzyl-1-(4-(4-trifluoromethyl)phenoxy)butylpiperidine;

**2-Benzyl-1-(4-(3-fluoro)phenoxy)butylpiperidine;

2-Benzyl-1-(3-(3-phenyl)propynyl)piperidine;

*2-Benzyl-1-[3-(4-trifluoromethyl)phenyl)propynyl]piperidine;

*2-(4-chlorophenyl)methyl-1-[4-(3-amino)phenyl)butynyl]piperidine;

**2-Benzyl-1-[2-hydroxy-3-(2-methyl)phenoxy]propylpiperidine;

**2-[(2-Ethoxy)phenoxy]methyl-1-(3-phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(3-amino)phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidine;

**2-Benzyl-1-(5-phenoxypentyl)piperidine;

**2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine;

**1-(2-(4-Aminophenoxy)ethyl)-2-benzylpiperidine;

**2-Benzyl-1-(2-(4-amino-3-nitrophenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(2-oxobenzimidazol-5-oxy)ethyl)piperidine;

**2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine;

**2-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy)propyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy)butyl)piperidine; and

2-[(4-chloro)phenoxy]methyl-1-(3-phenoxy)propylpiperidine.

Of the above-listed exemplary compounds, the more preferred compoundsare designated * and the most preferred are designated **.

The compounds of this invention may be prepared by methods known to oneof ordinary skill in the art or readily adaptable from such knownmethods without undue experimentation. Starting materials employed forthe preparation of the inventive compounds are readily available or thepreparation thereof is well within the knowledge and ability of one ofordinary skill.

The invention is also directed to a method for treating disordersresponsive to the selective blockade of NMDA receptor subtypes inanimals suffering thereof. Particular preferred embodiments of the2-substituted piperidine analogs for use in the method of this inventionare represented by previously defined formulae (III-VI) as well as bythe compound represented by formula (II): ##STR20## or apharmaceutically acceptable salt thereof, wherein Ar¹, Ar², R¹, R², mand n are the same as previously defined.

Exemplary preferred compounds that may be employed in the method of thisinvention include, without limitation:

*1,2-Dibenzylpiperidine;

2-Benzyl-1-(4-fluorophenyl)methylpiperidine;

2-Benzyl-1-(4-trifluoromethylphenyl)methylpiperidine;

*2-(4-chlorophenyl)methyl-1-(4-trifluoromethylphenyl)methylpiperidine;

2-Benzyl-1-(2-phenyl)ethylpiperidine;

2-Benzyl-1-(2-(3-fluoro)phenyl)ethylpiperidine;

*2-Benzyl-1-(2-(4-trifluoromethyl)phenyl)ethylpiperidine;

**2-(4-chlorophenyl)methyl-1-(2-(4-fluoro)phenyl)ethylpiperidine;

**2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenyl)ethylpiperidine;

**2-Benzyl-1-(3-phenyl)propylpiperidine;

*2-Benzyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidine;

**2-(4-chlorophenyl)methyl-1-(3-(3-trifluoromethyl)phenyl)propylpiperidine;

**2-Benzyl-1-(4-phenyl)butylpiperidine;

*2-Benzyl-1-(4-(3-trifluoromethyl)phenyl)butylpiperidine;

**2-(3,4-dichlorophenyl)methyl-1-(4-(4-trifluoromethyl)phenyl)butylpiperidine;

*2-Benzyl-1-(2-phenoxy)ethylpiperidine;

*2-Benzyl-1-(2-(4-trifluoromethyl)phenoxy)ethylpiperidine;

**2-Benzyl-1-(2-(3-amino)phenoxy)ethylpiperidine

**2-(4-chlorophenyl)methyl-1-(2-(3-amino)phenoxy)ethylpiperidine;

**2-Benzyl-1-(3-phenoxy)propylpiperidine;

*2-Benzyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine;

*2-(4-chlorophenyl)methyl-1-(3-(3-amino)phenoxy)propylpiperidine;

**2-Benzyl-1-(4-phenoxy)butylpiperidine;

*2-Benzyl-1-(4-(3-trifluoromethyl)phenoxy)butylpiperidine;

*2-Benzyl-1-(4-(3-amino)phenoxy)butylpiperidine;

2-Benzyl-1-(4-(2-trifluoromethy)phenoxy)butylpiperidine;

**2-Benzyl-1-(4-(4-trifluoromethyl)phenoxy)butylpiperidine;

**2-Benzyl-1-(4-(3-fluoro)phenoxy)butylpiperidine;

2-Benzyl-1-(3-phenyl)propynyl)piperidine;

*2-Benzyl-1-[3-(4-trifluoromethyl)phenyl)propynyl]piperidine;

*2-(4-chlorophenyl)methyl-1-[4-(4-(3-amino)phenyl)butynyl]piperidine;

**2-Benzyl-1-[2-hydroxy-3-(2-methyl)phenoxy]propylpiperidine;

**2-[(2-Ethoxy)phenoxy]methyl-1-(3-phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(3-amino)phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenoxy)propylpiperidine;

*2-[(2-Ethoxy)phenoxy]methyl-1-(3-(4-trifluoromethyl)phenyl)propylpiperidine;

**2-Benzyl-1-(5-phenoxypentyl)piperidine;

**2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine;

**1-(2-(4-Aminophenoxy)ethyl)-2-benzylpiperidine;

**2-Benzyl-1-(2-(4-amino-3-nitrophenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(2-oxobenzimidazol-5-oxy)ethyl)piperidine;

**2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidine;

**2-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy)propyl)piperidine;

**2-Benzyl-1-(2-(4-hydroxyphenoxy) butyl)piperidine; and

2-[(4-chloro)phenoxy]methyl-1-(3-phenoxy)propylpiperidine.

Of the above-listed exemplary compounds, the more preferred compoundsfor use in the method of this invention are designated * and the mostpreferred are designated **.

The compounds of the present invention are useful in treating orpreventing neuronal loss, neurodegenerative diseases and chronic pain.They are also useful as anticonvulsants and for inducing anesthesia, aswell as for treating epilepsy and psychosis. The therapeutic and sideeffect profiles of selective NMDA receptor subtype antagonists andagonists should be markedly different from the more non-selective typesof inhibitors. The subtype-selective analogs of the present inventionare expected to exhibit little or no untoward side effects caused bynon-selective binding with other receptors, particularly, the PCP andglutamate bindings sites associated with the NMDA receptor. In addition,selectivity for different NMDA receptor subtypes will reduce sideeffects such as sedation that are common to non-subtype-selective NMDAreceptor antagonists. The compounds of the present invention areeffective in treating or preventing the adverse consequences of thehyperactivity of the excitatory amino acids, e.g. those which areinvolved in the NMDA receptor system, by preventing the ligand-gatedcation channels from opening and allowing excessive influx of Ca⁺⁺ intoneurons, as occurs during ischemia.

Neurodegenerative diseases which may be treated with the compounds ofthe present invention include those selected from the group consistingof Alzheimer's disease, amyotrophic lateral sclerosis, Huntington'sdisease, Parkinson's disease and Down's syndrome.

The compounds of the present invention find particular utility in thetreatment or prevention of neuronal loss associated with multiplestrokes which give rise to dementia. After a patient has been diagnosedas suffering from a stroke, the compounds of the present invention maybe administered to ameliorate the immediate ischemia and prevent furtherneuronal damage that may occur from recurrent strokes.

Moreover, the compounds of the present invention are able to cross theblood/brain barrier which makes them particularly useful for treating orpreventing conditions involving the central nervous system.

The compounds of the invention find particular utility in treating orpreventing the adverse neurological consequences of surgery. Forexample, coronary bypass surgery requires the use of heart-lung machineswhich tend to introduce air bubbles into the circulatory system whichmay lodge in the brain. The presence of such air bubbles robs neuronaltissue of oxygen, resulting in anoxia and ischemia. Pre- orpost-surgical administration of the compounds of the present inventionwill treat or prevent the resulting ischemia. In a preferred embodiment,the compounds of the invention are administered to patients undergoingcardiopulmonary bypass surgery or carotid endarterectomy surgery.

The compounds of the present invention also find utility in treating orpreventing chronic pain. Such chronic pain may be the result of surgery,trauma, headache, arthritis, pain from terminal cancer or degenerativediseases. The compounds of the present invention also find particularutility in the treatment of phantom pain that results from amputation ofan extremity. In addition to treatment of pain, the compounds of theinvention are also expected to be useful in inducing anesthesia, eithergeneral or local anesthesia, for example, during surgery.

The subtype-selective NMDA receptor antagonists, agonists and modulatorsmay be tested for in vivo anticonvulsant activity after intraperitonealor intravenous injection using a number of anticonvulsant tests in mice(audiogenic seizure model in DBA-2 mice, pentylenetetrazol-inducedseizures in mice, maximum electroshock seizure test (MES) orNMDA-induced death). The compounds may also be tested in drugdiscrimination tests in rats trained to discriminate PCP from saline. Itis expected that most of the compounds of the present invention will notgeneralize to PCP at any dose. In addition, it is also expected thatnone of the compounds will produce a behavioral excitation in locomotoractivity tests in the mouse. It is expected that such results willsuggest that the subtype-selective NMDA receptor antagonists andagonists of the present invention do not show the PCP-like behavioralside effects that are common to NMDA channel blockers such as MK-801 andPCP or to competitive NMDA antagonists such as CGS 19755.

The subtype-selective NMDA receptor antagonists and agonists are alsoexpected to show potent activity in vivo after intraperitoneal andintravenous injection suggesting that these compounds can penetrate theblood/brain barrier.

Elevated levels of glutamate has been associated with glaucoma. Inaddition, it has been disclosed that glaucoma management, particularlyprotection of retinal ganglion cells, can be achieved by administeringto a patient a compound capable of reducing glutamate-inducedexcitotoxicity in a concentration effective to reduce theexcitotoxicity. See WO94/13275. Thus, the compounds of the presentinvention, which are expected to cross the blood-retina barrier, arealso expected to be useful in the treatment of glaucoma. Preferably, theinvention is directed to the treatment of patients which have primaryopen-angle glaucoma, chronic closed-angle glaucoma, pseudodoexfoliation, or other types of glaucoma or ocular hypertension.Preferably, the compound is administered over an extended period (e.g.at least six months and preferably at least one year), regardless of thechanges in the patient's intraocular pressure over the period ofadministration. The compounds of the present invention are also usefulin treating CMV retinitis, particularly in combination with antiviralagents. CMV afflicts the ganglion cell layer which may result in higherlevels of glutamate. Thus, NMDA receptor antagonists could blockretinitis by blocking the toxicity effect of high levels of glutamate.

Aminoglycoside antibiotics have been used successfully in the treatmentof serious Gram-negative bacterial infections. However, prolongedtreatment with these antibiotics will result in the destruction ofsensory hearing cells of the inner ear and consequently, inducepermanent loss of hearing. A recent study of Basile, et al. (NatureMedicine, 2: 1338-1344, 1996) indicated that aminoglycosides produce apolyamine-like enhancement of glutamate excitotoxicity through theirinteraction with the NMDA receptor. Thus, compounds of the presentinvention with NMDA receptor antagonist activity will be useful inpreventing aminoglycoside antibiotics-induced hearing loss byantagonizing their interaction with the receptor.

The compounds of the present invention are useful in treating headaches,in particular, migraine headaches. During migraine attack, a sensorydisturbance with unique changes of brain blood flow will result in thedevelopment of characteristic migraine auras. Since this uniquephenomena has been replicated in animal experiments withcortical-spreading depression (CSD) of Leao, A.A.P.J., Neurophysiol.7:359-390 (1944), CSD is considered an important phenomena in thepathophysiology of migraine with aura (Tepley et al., In: Biomagnetism,eds. S. Williamson, L. Kaufmann, pp. 327-330, Plenum Press, New York(1990)). The CSD is associated with the propagation (2˜6 mm/s) oftransient changes in electrical activity which relate to the failure ofion homoestatis in the brain, efflux of excitatory amino acids from theneurons and increased energy metabolism (Lauritzen, M., Acta Neurol.Scand. 76 (Suppl. 113): 4-40 (1987)). It has been demonstrated that theinitiation of CSD in a variety of animals, including humans, involvedthe release of glutamate and could be triggered by NMDA (Curtis et al.,Nature 191:1010-1011 (1961); and Lauritzen et al., Brain Res.475:317-327 (1988)). Subtype selective NMDA antagonists will betherapeutically useful for migraine headache because they can block CSDand subsequent pain and because of their expected low side effects,their ability to cross the blood brain barrier and their systemicbioavailability.

Bladder activity is controlled by parasympathetic preganglionic neuronsin the sacral spinal cord (DeGroat et al., J. Auton. Nerv. Sys.3:135-160(1981)). In humans, it has been shown that the highest densityof NMDA receptors in the spinal cord are located at the sacral level,including those areas that putatively contain bladder parasympatheticpreganglionic neurons (Shaw et al., Brain Research 539:164-168 (1991)).Because NMDA receptors are excitatory in nature, pharmacologicalblockade of these receptors would suppress bladder activity. It has beenshown that the noncompetitive NMDA receptor antagonist MK801 increasedthe frequency of micturition in rat (Vera and Nadelhaft, NeuroscienceLetters 134:135-138(1991)). In addition, competitive NMDA receptorantagonists have also been shown to produce a dose-dependent inhibitionof bladder and of urethral sphincter activity (U.S. Pat. No. 5,192,751).Thus, it is anticipated that subtype-selective NMDA receptor antagonistswill be effective in the treatment of urinary incontinence mediated bytheir modulation on the receptor channel activity.

Non-competitive NMDA receptor antagonist MK801 has been shown to beeffective in a variety of animal models of anxiety which are highlypredictive of human anxiety (Clineschmidt, B. V. et al., Drug Dev. Res.2:147-163 (1982)). In addition, NMDA receptor glycine site antagonistsare shown to be effective in the rat protentiated startle test (Anthony,E. W., Eur. J. Pharmacol. 250:317-324 (1993)) as well as several otheranimal anxiolytic models (Winslow, J. et al, Eur. J. Pharmacol.190:11-22 (1990); Dunn, R. et al., Eur. J. Pharmacol. 214:207-214(1992); and Kehne, J. H. et al, Eur. J. Pharmacol. 193:282-292 (1981)).

Glycine site antagonists, (+) HA-966 and 5,7-dichlorokynurenic acid werefound to selectively antagonize d-amphetamine induced stimulation wheninjected into rat nucleus accumbens but not in striatum (Hutson, P. H.et al., Br. J. Pharmacol. 103:2037-2044 (1991)). Interestingly, (+)HA-966 was also found to block PCP and MK801-induced behavioral arousal(Bristow, L. J. et al., Br. J. Pharmacal, 108:1156-1163 (1993)). Thesefindings suggest that a potential use of NMDA receptor channelmodulators, but not channel blockers, as atypical neuroleptics.

It has been shown that in an animal model of Parkinson's disease--MPP⁺or methamphetamine-induced damage to dopaminergic neurons--can beinhibited by NMDA receptor antagonists (Rojas et al., Drug Dev. Res.29:222-226 (1993); and Sonsalla et al, Science 243;398-400 (1989)). Inaddition, NMDA receptor antagonists have been shown to inhibithaloperidol-induced catalepsy (Schmidt, W. J. et al., Amino Acids1:225-237 (1991)), increase activity in rodents depleted of monoamines(Carlsson et al., Trends Neurosci. 13:272-276 (1990)) and increaseipsilateral rotation after unilateral substantia nigra lesion in rats(Snell, L. D. et al., J. Pharmacol. Exp. Ther. 235:50-57 (1985)). Theseare also experimental animal models of Parkinson's disease. In animalstudies, the antiparkinsonian agent amantadine and memantine showedantiparkinsonian-like activity in animals at plasma levels leading toNMDA receptor antagonism (Danysz, W. et al., J. Neural Trans. 7:155-166,(1994)). Thus, it is possible that these antiparkinsonian agents acttherapeutically through antagonism of an NMDA receptor. Therefore, thebalance of NMDA receptor activity maybe important for the regulation ofextrapyramidal function relating to the appearance of parkinsoniansymptoms.

It is well known to use opiates, e.g., morphine, in the medical field toalleviate pain. (As used herein, the term "opiates" is intended to meanany preparation or derivative of opium, especially the alkaloidsnaturally contained therein, of which there are about twenty, e.g.,morphine, noscapine, codeine, papaverine, and thebaine, and theirderivatives.) Unfortunately, with continued use, the body builds up atolerance for the opiate, and, thus, for continued relief, the patientmust be subjected to progressively larger doses. Tolerance developsafter both acute and chronic morphine administration (Kornetsky et al.,Science 162:1011-1012 (1968); Way et al., J. Pharmacol. Exp Ther.167:1-8 (1969); Huidobro et al., J. Pharmacol. Exp Ther. 198:318-329(1976); Lutfy et al., J. Pharmacol. Exp Ther. 256:575-580 (1991)). This,in itself, can be detrimental to the patient's health. Furthermore, atime can come when the tolerance is substantially complete and the painkilling properties of the drug are no longer effective. Additionally,administration of higher doses of morphine may lead to respiratorydepression, causing the patient to stop breathing. Seeking alternativedrugs to produce analgesia without development of tolerance or as anadjunct therapy to block tolerance without interference with analgesiais an active area of research.

Recent studies have suggested a modulatory role for the NMDA receptor inmorphine tolerance. (Trujillo et al., Science 251:85-87 (1991); Marek etal., Brain Res. 547:77-81 (1991); Tiseo et al., J. Pharmacol. Exp Ther.264:1090-1096 (1993); Lutfy et al., Brain Res. 616:83-88 (1993); Hermanet al., Neuropsychopharmacology 12:269-294 (1995).) Further, it has beenreported that NMDA receptor antagonists are useful for inhibiting opioidtolerance and some of the symptoms of opioid withdrawal. Thus, thepresent invention is also directed to the administration of thecompounds described herein to inhibit opiate tolerance and to treat orameliorate the symptoms of opiate withdrawal by blocking the glycineco-agonist site associated with the NMDA receptor.

Thus, the present invention is directed to compounds having highaffinity to a particular NMDA receptor subunit and low affinity to othersites such as dopamine and other catecholamine receptors, and σ sites.According to the present invention, those compounds having high bindingto a particular NMDA subunit exhibit an IC₅₀ of about 100 μM or less inan NMDA subunit binding assay (see Table 1). Preferably, the compoundsof the present invention exhibit a selective subunit IC₅₀ of 10 μM orless. Most preferably, the compounds of the present invention exhibit aselective subunit IC₅₀ of about 1.0 μM or less.

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount which is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically, thecompounds may be administered to mammals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the mammal beingtreated for anxiety disorders, e.g., generalized anxiety disorder,phobic disorders, obsessional compulsive disorder, panic disorder andpost traumatic stress disorders or for schizophrenia or other psychoses.Preferably, about 0.01 to about 10 mg/kg is orally administered to treator prevent such disorders. For intramuscular injection, the dose isgenerally about one-half of the oral dose. For example, for treatment orprevention of anxiety, a suitable intramuscular dose would be about0.0025 to about 15 mg/kg, and most preferably, from about 0.01 to about10 mg/kg.

In the method of treatment or prevention of neuronal loss in ischemia,brain and spinal cord trauma, hypoxia, hypoglycemia, and surgery, totreat or prevent glaucoma or urinary incontinence, as well as for thetreatment of Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, Parkinson's disease and Down's Syndrome, or in amethod of treating a disease in which the pathophysiology of thedisorder involves hyperactivity of the excitatory amino acids or NMDAreceptor-ion channel related neurotoxicity, the pharmaceuticalcompositions of the invention may comprise the compounds of the presentinvention at a unit dose level of about 0.01 to about 50 mg/kg of bodyweight, or an equivalent amount of the pharmaceutically acceptable saltthereof, on a regimen of 1-4 times per day. When used to treat chronicpain, migrane headache, to induce anesthesia, to treat or prevent opiatetolerance or to treat opiate withdrawal, the compounds of the inventionmay be administered at a unit dosage level of from about 0.01 to about50 mg/kg of body weight, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, on a regimen of 1-4 times per day. Of course,it is understood that the exact treatment level will depend upon thecase history of the animal, e.g., human being, that is treated. Theprecise treatment level can be determined by one of ordinary skill inthe art without undue experimentation.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets eachcontaining from about 0.1 to about 10, conveniently about 0.25 to 50 mgof the compound or its solvates.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Also included within the scope of the present invention are thenon-toxic pharmaceutically acceptable salts of the compounds of thepresent invention. Acid addition salts are formed by mixing a solutionof the particular selective NMDA receptor subtype antagonist or agonistof the present invention with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, and the like. Basic saltsare formed by mixing a solution of the particular 2-substitutedpiperidine analog of the present invention with a solution of apharmaceutically acceptable non-toxic base such as sodium hydroxide,potassium hydroxide, choline hydroxide, sodium carbonate and the like.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, or buccal routes.Alternatively, or concurrently, administration may be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesinclude, without limitation, flow-regulating agents and lubricants, forexample, silica, talc, stearic acid or salts thereof, such as magnesiumstearate or calcium stearate, and/or polyethylene glycol. Dragee coresare provided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetyl-cellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally include,for example, suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances which increase the viscosity of the suspensioninclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

The characterization of NMDA subunit binding sites in vitro has beendifficult because of the lack of selective drug ligands. Thus, thecompounds of the present invention may be used to characterize the NMDAsubunits and their distribution. Particularly preferredsubtype-selective NMDA receptor antagonists and agonists of the presentinvention which may be used for this purpose are isotopicallyradiolabelled derivatives, e.g., where one or more of the atoms arereplaced with ³ H, ¹¹ C, ¹⁴ C, ¹⁵ N or ¹⁸ F.

Electrophysiological Assays at NMDA Receptor Subunits

Preparation of RNA. cDNA clones encoding the NR1A, NR2A, NR2B, NR2C andNR2D rat NMDA receptor subtypes were provided by Dr. P. H. Seeburg (see,Moriyoshi et al., Nature (Lond.) 354:31-37 (1991); Kutsuwada et al.,Nature (Lond.) 358:36-41 (1992) Monyer et al., Science (Washington,D.C.) 256:1217-1221 (1992); Ikeda et al., FEBS Lett. 313:34-38 (1992);Ishii et al., J. Biol. Chem. 268:2836-2843 (1993) for details of theseclones or their mouse homologs). The clones were transformed intoappropriate host bacteria and plasmid preparations were made withconventional DNA purification techniques. A sample of each clone waslinearized by restriction enzyme digestion and cRNA was synthesized withT3 RNA polymerase. The cRNA was diluted to 400 ng/μl and stored in 1 μlaliquots at -80° C. until injection.

The Xenopus oocyte expression system. Mature female Xenopus laevis wereanaesthetized (20-40 min) using 0.15% 3-aminobenzoic acid ethyl ester(MS-222) and 2-4 ovarian lobes were surgically removed. Oocytes atdevelopmental stages IV-VI (Dumont, J. N., J. Morphol. 136:153-180(1972)), were dissected from the ovary still surrounded by envelopingovarian tissues. Follicle-enclosed oocytes were micro-injected with 1:1mixtures of cRNA:NR1A+NR2A, 2B, 2C or 2D; injecting ˜2,5, or 20 ng ofRNA encoding each receptor subunit. NR1A encoding cRNA was injectedalone at ˜20 ng. Oocytes were stored in Barth's medium containing (inmM):NaCl, 88; KCl, 1; CaCl₂, 0.41; Ca(NO₃)₂, 0.33; MgSO₄, 0.82 NaHCO₃,2.4; HEPES 5, pH 7.4, with 0.1 mg/ml gentamicin sulphate. While oocyteswere still surrounded by enveloping ovarian tissues the Barth's mediumwas supplemented with 0.1% bovine serum. Oocytes were defolliculated 1-2days following injections by treatment with collagenase (0.5 mg/ml SigmaType I for 0.5-1 hr) (Miledi and Woodward, J. Physiol. (Lond.)416:601-621 (1989)) and subsequently stored in serum-free medium.

Electrical recordings were made using a conventional two-electrodevoltage clamp (Dagan TEV-200) over periods ranging between 3-14 daysfollowing injection.

(Woodward et al., Mol. Pharmacol. 41:89-103 (1992)). Oocytes were placedin a 0.1 ml recording chamber continuously perfused (5-15 ml min⁻¹) withfrog Ringer's solution containing (in mM):NaCl, 115; KCl, 2; CaCl₂, 1.8;HEPES, 5; pH 7.4. Drugs were applied by bath perfusion. Using oocytesexpressing different subunit combinations of NMDA receptor, NMDAcurrents were activated by co-application of glutamate and glycine.Inhibitory potency of the novel antagonists was assessed on responseselicited by fixed concentrations of glutamate and glycine, by measuringreductions in current induced by progressively increasing concentrationsof antagonists.

Concentration-inhibition curves were fit with equation 1.

    I/I.sub.control =1/(1+([antagonist]/10.sup.-pIC50).sup.n   Eq. 1

in which I_(control) is the current evoked by agonists alone, pIC₅₀=-log IC₅₀, IC₅₀ is the concentration of antagonist that produces halfmaximal inhibition, and n is the slope factor. (De Lean et al., Am. J.Physiol. 235:E97-E102(1978)). For incomplete curves analysis by fittingwas unreliable and IC₅₀ values were calculated by simple regression overlinear portions of the curves (Origin: Microcal Software).

Maximal Electroshock-induced Seizures

Seizures were induced by application of current (50 mA, 60 pulses/sec,0.8 sec pulse width, 1 sec duration, d.c.) through saline-coated cornealelectrodes using a Ugo Basile ECT device (Model 7801). Mice wererestrained by gripping the loose skin on their dorsal surface,electrodes were held lightly against the two cornea, then current wasapplied and mice were observed for a period of up to 30 sec for theoccurrence of a tonic hindlimb extensor response. A tonic seizure wasdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results were treated in a quantal manner.

The examples which follow are intended as an illustration of certainpreferred embodiments of the invention, and no limitation of theinvention is implied.

EXAMPLE 1 2-Benzylpiperdine Hydrochloride ##STR21##

A solution of 2-benzylpyridine (2.0 g, 12 mmol) in MeOH (50 mL)containing conc. HCl (1 mL) was hydrogenated in a Parr apparatus over Pt(PtO₂, 30 mg) at 25° C. The reaction was allowed to proceed at 22 psifor 5 h, 45 psi for 4 h, then overnight at 22 to 12 psi. The catalystwas removed by filtration and the solvent was removed in vacuo to give asyrup. Absolute EtOH (50 mL) was added and then evaporated in vacuo.This was repeated to give a near colorless solid. The solid wastriturated with ether (2×20 mL) and dried in vacuo to give a colorlesspowder (2.36 g, 94% yield); mp 128-131° C., lit. 125-130° C. (videsupra); ¹ H NMR (D₂ O) 1.45-2.05 (m, 6H), 2.80-3.05 (m, 3H), 3.27-3.45(m, 2H) 7.26-7.46 (m, 5H).

EXAMPLE 2 1,2-Dibenzylpiperidine, Hydrobromide ##STR22##

A mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol), K₂CO₃ (652 mg, 4.72 mmol) and benzyl bromide (605 mg, 3.54 mmol) in CH₃ CN(25 mL) was stirred at reflux under N₂ for 48 h. The reaction wasallowed to cool to room temperature and was added to 5% aqueous HCl (100mL). The resulting cloudy solution was extracted with CHCl₃ (3×50 mL).The extract was washed with 10% aqueous NH₄ OH (2×50 mL) and water (2×50mL), filtered through cotton and the solvent removed in vacuo.Purification was effected by silica gel chromatography (2.5×30 cm)column, CHCl₃ elution). Solvent removal from the pure fractions yieldeda cloudy amber oil. This was dissolved in MeOH (5 mL, cloudy solution),filtered through celite (clear solution) and the MeOH removed in vacuoto yield a clear amber oil (304 mg, 48%); ¹ H NMR (CDCl₃) 1.20-1.70 (m,6H), 2.15-2.30 (m, 1 H), 2.58-2.82 (m, 3 H), 3.11-3.25 (m, 1 H), 3.49(d, J=13.5 Hz, 1 H), 4.06 (d, J=13.5 Hz, 1 H), 7.10-7.41 (m, 10 H).

A solution of the free base (250 mg, 942 mmol) in MeOH (5 mL) wastreated with a dilute solution of HBr in MeOH until the amine solutionbecame permanently acidic (pH paper). The solvent was removed in vacuoto give an oil. This was dissolved in benzene (20 mL) and evaporated invacuo. The resulting oil was dissolved in benzene and the solution addeddrop wise to vigorously stirred hexanes (175 mL). The resultingprecipitate was collected, washed with hexanes (3×2 mL) and dried invacuo to yield a beige powder (227 mg, 70%, mp 170-172° C.; ¹ H NMR(CDCl₃) 1.15-4.70 (m, 13 H), 7.08-7.90 (m, 10 H), 11.55 (bs, 1 H).

EXAMPLE 3 2-Benzyl-1-(2-phenylethyl)piperidine, Hydrobromide ##STR23##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),K₂ CO₃ (652 mg, 4.72 mmol) and 2-bromoethylbenzene (655 mg, 3.54 mmol)in CH₃ CN (25 mL) there was obtained the free base as a clear amber oil(414 mg, 63%,); ¹ H NMR (CDCl₃) 1.18-1.89 (m, 6 H), 2.46-3.08 (m, 8 H),3.15 (dd, J1=12.9 Hz, J2=3.6 Hz, 1 H), 7.14-7.36 (m, 10 H).

The HBr salt was a colorless powder; mp 155-158° C.; ¹ H NMR (CDCl₃)1.30-3.78 (m, 15 H), 7.14-7.38 (m, 10 H), 11.50 & 11.69 (overlapping bs,1 H).

An analytical sample was prepared by crystallization from 2-butanone; mp162.5-164.5° C. Anal. Calcd. for C₂₀ H₂₆ BrN; C, 66.66; H, 7.27; N,3.89. Found: C, 66.91; H, 7.18; N, 3.84.

EXAMPLE 4 2-Benzyl-1-(3-phenylpropyl)piperidine, Hydrobromide ##STR24##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),K₂ CO₃ (652 mg, 4.72 mmol) and 3-phenylpropyl bromide (705 mg, 3.54mmol) in CH₃ CN (25 mL) there was obtained the free base as a clearamber oil (425 mg, 61%); ¹ H NMR (CDCl₃) 1.10-1.70 (m, 6 H), 1.86 (m,2H), 2.30-2.90 (m, 8 H), 3.30 (dd, J1=12.6 Hz, J2=3.0 Hz, 1 H),7.10-7.35 (m, 10 H).

The HBr salt was colorless powder; mp 153-155° C.; ¹ H NMR (CDCl₃) γ1.20-3.70 (m, 17 H), 7.08-7.36 (m, 10 H), 11.30 (bs, 1 H).

Analytical sample mp 155-157° C. Anal. Calcd. for C₂₀ H₂₈ BrN: C, 67.38;H, 7.54; N,3.74. Found: C, 67.19; H, 7.73; N, 3.75.

EXAMPLE 5a 2-Benzyl-1-(4-phenylbutyl)piperidine), Citric Acid Salt##STR25##

From 2-benzylpiperidine hydrochloride (250 mg, 1.18 mmol), K₂ CO₃ (326mg, 2.36 mmol) and 1-phenyl-4-tosylbutane (449 mg, 1.50 mmol) in CH₃ CN(25 mL) there was obtained the free base as a clear amber oil; (286 mg,79%) ¹ H NMR (CDCl₃) 1.15-1.75 (m, 10 H), 2.30-2.90 (m, 8 H), 3.09 (dd,J1=12.6 Hz, J2=2.7 Hz, 1 H), 7.11-7.37 (m, 10 H); HRMS calcd for C₂₂ H₂₉N: 307.2299. Found: 307.2317.

A solution of the free base (272 mg, 885 mmol) in MeOH (5 mL) wascombined with a solution of citric acid monohydrate (195 mg, 929 mmol)in MeOH (5 mL). The resulting solution was stirred for 5 min and thesolvent was removed in vacuo to give a foamy solid. This was trituratedwith ether (10 mL) to give a powdery solid. The solid was collected,washed with ether (10×1 mL, tacky at this point) and dried in vacuo(0.05 Torr, 40° C.). The material became a solid mass during drying.Scraping with a spatula gave a powder (295 mg, 67%); mp 43-57° C.; ¹ HNMR (D₂ O) 1.40-2.00 (m, 10H), 2.60-3.75(m, 13 H), 7.15-7.50 (m, 10 H).

EXAMPLE 5b 2-Benzyl-1-(4-phenylbutyl)piperidine, Hydrobromide ##STR26##

The HBr salt was obtained as a colorless powder; mp 133-135° C.; ¹ H NMR(CDCl₃) 1.40-3.65 (m, 19 H), 7.04-7.35 (m, 10 H), 11.25 (bs, 1 H).

EXAMPLE 6a 2-Benzyl-1-(2-phenoxyethyl)piperidine, Citric Acid Salt##STR27##

From 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),2-phenoxyethyl tosylate (1.04 g, 3.54 mmol and K₂ CO₃ (652 mg, 4.72mmol) there was obtained the free base as a clear amber oil; (417 mg,60% ¹ H NMR (CDCl₃) 1.10-1.70 (m, 6 H), 2.4-3.3 (m, 7H), 4.12 (m, 2 H),6.90-7.32 (m, 10 H); HRMS calcd for C₂₀ H₂₅ NO; 295.1936. Found:295.1950.

The citric acid salt was obtained as a powder; mp 55-75° C.; ¹ H NMR (D₂O) 1.35-2.00 (m, 6 H), 2.70-4.05 (m, 11 H), 4.3-4.5 (m, 2 H), 6.90-7.45(m, 10 H); IR (KBr) 2952, 1729, 1599, 1588, 1497, 1400, 1239, 1082, 756,701, 692 cm⁻¹.

EXAMPLE 6b 2-Benzyl-1-(2-phenoxyethyl)piperidine Hydrobromide ##STR28##

The HBr salt was obtain as a colorless powder; mp 119-121° C.; ¹ H NMR(CDCl₃) 1.30-4.80 (m, 15 H), 6.85-7.35 (m, 10 H), 11.57 and 11.74(overlapping broad singlets, 1 H).

Analytical sample; mp 117-120° C. Anal. Calcd. for C₂₁ H₂₈ BrNO: C,64.61; H, 7.23; N, 3.59. Found: C, 64.58; H, 7.24; N, 3.62.

EXAMPLE 7 2-Benzyl-1-(3-phenoxypropyl)piperidine Hydrobromide ##STR29##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),K₂ CO₃ (652 mg, 4.72 mmol) and 3-phenoxypropyl bromide (761 mg, 3.54mmol) in CH₃ CN (25 mL) there was obtained the free base as a clearamber oil; (598 mg, 82%); ¹ H NMR (CDCl₃) 1.10-1.70 (m, 6 H), 1.95-2.08(m, 2 H), 2.32-3.04 (m, 6 H), 3.10 (dd, J1=12.6 Hz,J2=3.0 Hz, 1 H), 4.01(t, J=6.3 Hz, 2 H), 6.88-7.32 (m, 10 H).

The HBr salt was obtained as a colorless powder; mp 119-121° C.; ¹ H NMR(CDCl₃) 1.45-2.21 (m, 6 H), 2.40-2.79 (m, 3 H), 3.15-3.72 (m, 6 H), 4.15(t, J=5.25 Hz, 2 H), 6.85-7.35 (m, 10 H), 11.47 (bs, 1 H). Anal. Calcd.for C₂₁ H₂₈ BrNO: C, 64.61; H, 7.23; N, 3.59. Found: C, 64.58; H, 7.24;N, 3.62.

EXAMPLE 8a 2-Benzyl-1-(4-phenoxybutyl)piperidine, Citric Acid Salt##STR30##

From 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol) and K₂ CO₃(652 mg, 4.72 mmol) and 4-phenoxybutyl bromide (811 mg, 3.54 mmol) inCH₃ CN (50 mL), there was obtained the free base as a clear amber oil;(594 mg, 78); ¹ H NMR (CDCl₃) 1.10-1.90 (m, 10 H), 2.30-2.90 (m, 6 H),3.10 (dd, J1=12.9 Hz, J2=3.0 Hz, 1 H), 4.01 (t, J=6.0 Hz, 2 H),6.88-7.34 (m, 10 H); HRMS calcd for C₂₂ H₂₉ NO: 323.2249. Found:323.2259.

The citric acid salt was obtained as a beige powder; mp 42-56° C.; ¹ HNMR (D₂ O) 1.45-2.10 (m, 10 H), 2.80-3.80 (m, 11 H), 4.05-4.25 (m, 2 H),6.95-7.50 (m, 10 H).

EXAMPLE 8b 2-Benzyl-1-(4-phenoxybutyl)piperidine Hydrobromide ##STR31##

HBr salt was obtained as a a colorless powder; mp 100-103° C.; ¹ H NMR(CDCl₃) 1.25-3.70 (m, 17 H), 3.92-4.10 (m, 2 H), 6.81-7.35 (m, 10 H),11.27 (bs, 1 H). Anal. Calcd. for C₂₂ H₃₀ BrNO: C, 65.34; H, 7.48; N,3.46. Found: C, 65.29; H, 7.78; N, 3.41.

EXAMPLE 9 4-(o-(Trifluoromethyl)phenoxy)-1-bromobutane ##STR32##

A mixture of α,α,α-trifluoro-p-cresol (2.22 g, 13.7 mmol), K₂ CO₃ (1.99g, 14.4 mmol) and 1,4-dibromobutane (14.5 g, 68.5 mmol) in CH₃ CN (50mL) was stirred at ref lux under N₂ for 24 h. The reaction was allowedto cool to 25° C. and then added to water (100 mL). The resultingbiphasic mixture was extracted with CHCl₃ 3×50 mL). The extract waswashed with water (1×50 mL), saturated NaHCO₃ (2×50 mL) and water (1×50mL), filtered through cotton and the solvent removed in vacuo to give anorange liquid. The excess 1,4-dibromobutane was removed by vacuumdistillation (5 Torr, 72-78° C.). The still pot residue, which containedthe product was subjected to chromatography on silica gel (2.5×30 cm)with CHCl₃ elution, yielded a colorless liquid; (2.75 g, 68%); ¹ H NMR(CDCl₃) 1.89-2.17 (m, 4 H), 3.50 (t, J=6.3 Hz, 2 H), 4.09 (t, J=5.7 Hz,2 H), 6.92-7.05 (m, 2 H), 7.48 (t, J=7.8 Hz, 1 H), 7.56 (d, J=7.8 Hz, 1H).

EXAMPLE 10 2-Benzyl-1-(4-(o-(trifluoromethyl) phenoxy)butyl)piperidineHydrobromide ##STR33##

From 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol), K₂ CO₃ (652mg, 4.72 mmol) and 4-(o-(trifluoromethyl)phenoxy)-1-bromobutane (841 mg,2.83 mmol) in CH₃ CN (25 mL) there was obtained the free bases as aclear amber oil; (570 mg, 62%), ¹ H NMR (CDCl₃) 1.15-1.90 (m, 10 H),2.35-2.95 (m, 6 H), 3.09 (dd, J1=12.6 Hz, J2=2.7 Hz, 1 H), 4.08 (t,J=5.4 Hz, 2 H), 6.93-7.31 (m, 7 H), 7.47 (t, J=5.1 Hz, 1 H), 7.56 (d,J=7.5 Hz, 1 H).

The HBr salt was obtained as a colorless powder; mp 136-140° C.; ¹ H NMR(CDCl₃) 1.25-3.69 (m, 17 H), 4.02-4.21 (m, 2 H), 6.94-7.34 (m, 7 H),7.50 (t, J=7.8 Hz, 1 H), 7.56 (d, J=7.8 Hz, 1 H), 11.24 (bs, 1 H). Anal.Calcd. for C₂₃ H₂₉ BrF₃ NO: C, 58.48; H, 6.19; N, 2.97. Found: C, 58.81;H, 6.32; N, 2.87.

EXAMPLE 11 4-(m-(Trifluoromethyl)phenoxy)-1-bromobutane ##STR34##

From a mixture of α,α,α-trifluoro-p-cresol (5.00 g, 30.8 mmol), K₂ CO₃(4.47 g, 32.3 mmol) and 1,4-dibromobutane (33.3 g, 154 mmol) in CH₃ CN(250 mL) there was obtained the bromide as a near colorless liquid;(7.50 g, 82% ¹ H NMR (CDCl₃) 1.89-2.15 (m, 4 H), 3.50 (t, J=6.3 Hz, 2H), 4.03 (t, J=6.0 Hz, 2 H), 7.03-7.25 (m, 3 H), 7.38 (dd, J1=7.9,J2=8.0 Hz, 1 H).

EXAMPLE 12 2-Benzyl-1-(4-(m-(trifluoromethyl)phenoxy)butyl)piperidine,Hydrobromide ##STR35##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),K₂ CO₃ (652 mg, 4.72 mmol) and4-(m-(trifluoromethyl)phenoxy)-1-bromobutane (1.05 g, 3.54 mmol) in CH₃CN (25 mL) there was obtained the free base as a clear amber oil; (672mg, 72%); ¹ H NMR (CDCl₃) 1.15-1.91 (m, 10 H), 2.29-2.89 (m, 6 H), 3.07(dd, J1=9.8 Hz, J2=3.2 Hz, 1 H), 4.01 (t, J=6.0 Hz, 2 H), 7.01-7.41 (m,9 H).

The HBR salt was obtained as a colorless powder; mp 142.5-144° C.; ¹ HNMR (CDCl₃) 1.25-3.70 (m, 17 H), 3.95-4.12 (m, 2 H), 7.00-7.18 (m, 9 H),11.40 (bs, 1 H); Analytical sample; mp 143.5-144.5° C. Anal. Calcd. forC₂₃ H₂₉ BrF₃ NO: C, 58.48; H, 6.19; N, 2.97. Found: C, 58.38; H, 6.23;N, 2.87.

EXAMPLE 13 4-(p-(Trifluoromethyl)phenoxy)-1-bromobutane ##STR36##

From a mixture of α,α,α-trifluoro-p-cresol (5.04 g, 31.1 mmol), K₂ CO₃(4.50 g, 32.6 mmol) and 1,4-dibromobutane (18.5 mL, 33.5 g, 155 mmol) inCH₃ CN (100 mL) there was obtained a colorless liquid; (6.70 g, 72%, ¹ HNMR (CDCl₃) 1.89-2.15 (m, 4 H), 3.50 (t, J=6.3 Hz, 2 H), 4.03 (t, J=6.0Hz, 2 H), 6.94 (d, J=8.4 Hz, 2 H), 7.54 (d, J=8.4 Hz, 2 H).

EXAMPLE 14 2-Benzyl-1-(4-(p-(trifluoromethyl)phenoxy)butyl)piperidine,Hydrobromide ##STR37##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol,K₂ CO₃ (652 mg, 4.72 mmol) and4-(p-(trifluoromethyl)phenoxy)-1-bromobutane (1.05 g, 3.54 mmol) in CH₃CN (25 mL) there was obtained the free base as a clear amber oil; (610mg, 66%), ¹ H NMR (CDCl₃) 1.15-1.91 (m, 10 H), 2.29-2.89 (m, 6 H), 3.07(dd, J1=12.9 Hz, J2=3.2 Hz, 1 H), 4.02 (t, J=6.00 Hz, 2 H); 6.95 (d,J=8.7 Hz, 2 H), 7.12-7.32 (m, 5 H), 7.54 (d, J=8.4 Hz, 2 H).

The HBr salt was obtained as a colorless powder; mp 130-134° C.; ¹ H NMR(CDCl₃) 1.25-3.70 (m, 17 H), 3.95-4.12 (m, 2 H), 6.88-6.95 (m, 2 H),7.14-7.37 (m, 5 H), 7.54 (d, J=8.4 Hz, 2 H), 11.33 (bs, 1 H). Anal.Calcd. for C₂₃ H₂₉ BrF₃ NO: C, 58.48; H, 6.19; N, 2.97. Found: C, 58.52;H, 6.25; N, 2.85.

EXAMPLE 15 4-(m-Fluorophenoxy)-1-bromobutane ##STR38##

From a mixture of 3-fluorophenol (5.00 g, 44.6 mmol), K₂ CO₃ (6.47 g,48.6 mmol) and 1,4-dibromobutane (26.6 mL, 48.1 g, 223 mmol) in CH₃ CN(200 mL) there was obtained the bromide as a colorless liquid; (7.30 g,66%); ¹ H NMR (CDCl₃) 1.89-2.15 (m, 4 H), 3.49 (t, J=6.3 Hz, 2 H), 3.99(t, J=6.0 Hz, 2 H), 6.55-6.71 (m, 3 H), 7.21 (dd, J1=J2=7.8 Hz, 1 H).

EXAMPLE 16 2-Benzyl-1-(4-(m-fluorophenoxy)butyl)piperidine, Hydrobromide##STR39##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),K₂ CO₃ (652 mg, 4.72 mmol) and 4-(m-fluorophenoxy)-1-bromobutane (874mg, 3.54 mmol) in CH₃ CN (25 mL) there was obtained the free base as aclear amber oil; (610 mg, 76%) ¹ H NMR (CDCl₃) 1.10-1.95 (m, 10 H),2.28-2.95 (m, 6 H), 3.12 (dd, J1=12 Hz, J2=3.3 Hz, 1 H), 4.00 (t, J=6.0Hz, 2 H); 6.60-6.75 (m, 4 H), 7.15-7.36 (m, 5H).

The HBr salt was obtained as a colorless powder; mp 119-123° C.; ¹ H NMR(CDCl₃) 1.20-3.75 (m, 17 H), 3.95-4.12 (m, 2 H), 6.55-6.72 (m, 3 H),7.14-7.37 (m, 6 H), 11.31 (bs, 1 H). Anal. Calcd. for C₂₂ H₂₉ BrFNO: C,62.56; H, 6.92; N, 3.32. Found: C, 62.58; H, 6.89; N, 3.28.

EXAMPLE 17 2-[(2-Ethoxy)phenyoxy]methyl-1-(3-phenoxy)propylpiperidine##STR40##

A mixture of 2-[(2-ethoxy)phenoxymethylpiperidine (3 mmol),1-bromo-3-phenoxypropane (5 mmol) and potassium carbonate (1 g) inacetonitrile (200 mL) was heated at reflux for 6 h. After diluting withwater, the product was extracted with chloroform and purified by columnchromatography.

EXAMPLE 18 2-Benzyl-1-[2-hydroxy-3-(2-methyl)phenoxy]propylpiperidine##STR41##

A mixture of 2-benzylpiperidine (2 mmol) and3-(2-methylphenoxy)propaneoxide (3 mmol) in acetonitrile was heated at60° C. for 12 h. The solvent was removed by rotoevaporation, and theproduct purified by column chromatography.

EXAMPLE 19 2-[1-hydroxy-2-phenyl]ethyl-1-(3-phenoxy)-propylpiperidine##STR42## A mixture of 1-benzyl-2-piperidine carboxaldehyde and benzylmagnesium bromide in tetrahydrofuran is reacted at about 0° C. under anitrogen atmosphere. The reaction is quenched with water and thereaction product 2-[1-hydroxy-2-phenyl]ethyl-1-phenylpiperidine istreated with 10% palladium on carbon under a hydrogen atmosphere toprovide 2-[1-hydroxy-2-phenyl]ethylpiperidine. A mixture of thisreaction product, 1-bromo-3-phenoxypropane and potassium carbonate inacetonitrile is heated at reflux for about 6 hours to provide the titledcompound. EXAMPLE 20 2-Benzyl-1-(5-phenoxypentyl)piperidine Hydrobromide##STR43##

A) 1-Bromo-5-phenoxypentane. From a mixture of phenol (1.00 g, 10.6mmol,) K₂ CO₃ (1.52 g, 11.0 mmol, and 1,5-dibromopentane (12.2 g, 53mmol, ) in CH₃ CN (50 mL) there was obtained a colorless liquid; (1.47g, 57%); ¹ H NMR (CDCl₃) 1.55-2.02 (m, 6 H), 3.45 (t, J=6.6 Hz, 2 H),3.98 (t, J=6.3 Hz, 2 H), 6.87-6.97 (m, 3 H), 7.24-7.33 (m, 2 H).

B) 2-Benzyl-1-(5-phenoxypentyl)piperidine hydrobromide. From a mixtureof 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol), K₂ CO₃ (652 mg,4.72 mmol, ) and 1-bromo-5-phenoxypentane (860 mg, 3.54 mmol) in CH₃ CN(25 mL) there was obtained the free amine as a clear amber oil; (568 mg,71%); ¹ H NMR (CDCl₃), 1.15-1.90 (m, 12 H), 2.29-2.89 (m, 6 H), 3.08(dd, J1=12.6 Hz, J2=3.3 Hz, 1 H), 3.97 (t, J=6.3 Hz, 2 H), 6.85-7.33 (m,10 H).

The hydrobromide salt was obtained as a colorless powder mp 137.5-139.5°C. ¹ H NMR (CDCl₃) 1.25-3.68 (m, 19 H), 3.88-4.05 (m, 2 H), 6.84-7.35(m, 10 H), 11.29 (bs, 1 H). Anal. Calcd for C₂₃ H₃₂ BrNO: C, 66.02; H,7.71; N. 3.35. Found: C, 66.23; H. 7.72; N. 3.31.

EXAMPLE 21 2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine Hydrobromide##STR44##

A) 1-Bromo-2-(4-nitrophenoxy)ethane. From a mixture of 4-nitrophenol(10.0 g, 71.9 mmol), K₂ CO₃ (10.4 g, 75.5 mmol) and 1,2-dibromoethane(31.0 mL, 67.6 g, 360 mmol in dimethylformamide (DMF) (50 mL) there wasobtained a very pale yellow solid; (6.77 g, 38%); mp 64-66° C.; ¹ H NMR(CDCl₃) 3.68 (t, J=6.0 Hz, 2 H), 4.39 (t, J-6.0 HZ, 2 H), 6.99 (d, J=9.3Hz, 2 H), 8.22 (d, J=9.3 Hz, 2 H).

B) 2-Benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide. From amixture of 2-benzylpiperidine hydrochloride (1.00 g, 4.72 mmol), K₂ CO₃(1.30 g, 9.44 mmol) and 1-bromo-2-(4-nitrophenoxy)ethane (1.17 g, 4.96mmol) in CH₃ CN (50 mL) there was obtained the hydrobromide as a paleyellow solid (888 mg, 45%); mp 180-182° C., ¹ H NMR (CDCl₃) 1.35-2.42(m, 6 H), 2.75-405 (m, 7 H), 4.50-4.95 (m, 2 H), 6.95-7.37 (m, 7H),8.15-8.26 (m, 2 H), 11.72 and 11.88 (overlapping bs, 1 H). Anal. Calcdfor C₂₀ H₂₅ BrN₂ O₃ : C, 57.01; H, 5.98: N, 6.65. Found: C, 57.16; H,6.01; N, 6.61.

EXAMPLE 22 1-(2-(4-Aminophenoxy)ethyl)-2-benzylpiperidine Dihydrobromide##STR45##

A mixture of 2-benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide(500 mg, 1.19 mmol) and Pd/C (10%, 50 mg, Aldrich) in MeOH (25 mL) wasshaken under H₂ (20-30 psi, Parr) for 2 h at 25° C. The catalyst wasremoved by filtration (Celite). The resulting solution was acidifiedwith a dilute solution of HBr in MeOH (pH paper to red). The MeOH wasremoved in vacuo (rotoevaporator, 35-40° C.) to give a syrup. Ether (45mL) was added and the resulting mixture was vigorously stirred at 25° C.for 24 h. A yellow suspension was obtained. The solid was collected,washed with ether (3×2 mL) and dried in vacuo (0.005 Torr, 56° C.) togive a beige powder (358 mg, 64%): mp 130° C.; ¹ H NMR (DMSO-d₆)1.28-1.95 (m, 6 H), 2.69-3.95 (m, 7 H), 4.60-4.55 (m, 2 H), 7.08-7.42(m, 9 H), 9.60-10.25 (m, 4 H); HRMS Calcd for C₂₀ H₂₆ N₂₀ : 310.2045.Found: 310.2040.

EXAMPLE 23 2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)pyridiniumBromide ##STR46##

From a solution of 2-(4-chlorobenzyl)pyridine (500 mg, 2.45 mmol) and2-(4-fluorophenoxy)ethyl bromide (537 mg, 2.45 mmol) in CH₃ CN (5 mL)was obtained the title compound as a colorless powder (271 mg, 26%), mp179-180° C.; ¹ H NMR (CDCl₃) 4.56 (t, J=4.8 Hz, 2H), 4.91 (s, 2H), 5.57(t, J=4.8 Hz, 2H), 6.74-6.81 (m, 2H), 6.89-6.97 (m, 2H), 7.23-7.30 (m,2H), 7.36-7.40 (m, 2H), 7.50 (dd, J=8.1 and 1.2 Hz, 1H), 7.96 (dt, J=6.9and 1.2 Hz, 1H), 8.28 (dt, J=7.8 and 1.5 Hz, 1H), 9.31 (dd, J=6.0 and1.2 Hz, 1H); Anal. Calcd for C₂₀ H₁₈ BrClFNO·H₂ O: C, 54.50; H, 4.57; N,3.18. Found: C, 54.70; H, 4.38; N, 3.14.

EXAMPLE 24 2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidineHydrochloride ##STR47##

A) 2-(4-Chlorobenzyl)piperidine hydrochloride. A mixture of2-(4-chlorobenzyl)pyridine (2.10 g, 10.3 mmol) in MeOH (50 mL)containing concd HCl (2 mL) and PtO2 (30 mg) was hydrogenated (Parr) at10 to 20 psi for 24 h at 25° C. The catalyst was removed by filtration(Celite). The solvent was removed from the filtrate to give an oil,which was further dried in vacuo (H₂ O aspirator, 60° C.) to give asolid. The solid was triturated with ether (50 mL) and was collected anddried in vacuo (100° C., 0.005 Torr) to yield the title compound as apale beige powder (2.41 g, 95%): mp 172-175° C.; ¹ H NMR (D₂ O)1.38-1.72 (m, 3H), 1.77-2.02 (m, 3H), 2.83-3.03 (m, 3H), 3.36 (d, J=11Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.40 (d, J=7.8 Hz, 2H).

B) 2-(4-Chlorobenzyl)-1-(2-(4-fluorophenoxy)ethyl)piperidinehydrochloride. From a mixture of 2-(4-chlorobenzyl)piperidinehydrochloride (500 mg, 2.03 mmol), 2-(4-fluorophenoxy)ethyl bromide (467mg, 2.13 mmol) and K₂ CO₃ (575 mg, 4.16 mmol) in CH₃ CN (20 mL) the freebase of the title compound was obtained as an amber oil (445 mg, 63%): ¹H NMR (CDCl₃) 1.15-1.35 (m, 2H), 1.42-1.70 (m, 4H), 2.42-3.20 (m, 7H),3.95-4.13 (m, 2H), 6.82-7.02 (m, 4H), 7.10 (d, J=8.4 Hz, 2H), 7.24 (d,J=8.4 Hz, 2H).

The hydrochloride was obtained as a colorless powder (395 mg, 80%), mp163-165° C.; ¹ H NMR (CDCl₃) 1.30-2.35 (m, 6H), 2.62-3.80 (m, 7H),4.30-4.70 (m, 2H), 6.82-7.32 (m, 8H), 12.67 and 12.83 (overlapping bs,1H); Anal. Calcd for C₂₀ H₂₄ Cl₂ FNO: C, 62.51; H, 6.29; N, 3.64. Found:C, 62.51; H, 6.42; N, 3.47.

EXAMPLE 25 2-(4-Chlorobenzyl)-1-(2-(4-hydroxyphenoxy)ethyl)piperidineHydrochloride ##STR48##

From a mixture of 2-(4-chlorobenzyl)piperidine hydrochloride (500 mg,2.03 mmol), 2-(4-hydroxyphenoxy)ethyl bromide (462 mg, 2.13 mmol) andNaHCO₃ (349 mg, 4.16 mmol) in CH₃ CN (20 mL) was obtained the free baseof the title compound as a foam (572 mg): ¹ H NMR (CDCl₃) 1.20-1.35 (m,2H), 1.43-1.70 (m, 4H), 2.47-2.64 (m, 2H), 2.68-2.80 (m, 1H), 2.92-3.21(m, 4H), 3.87-4.13 (m, 2H), 6.72 (d, J=9.3 Hz, 2H), 6.87 15. (bs, 1H),6.76 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H).

The hydrochloride was obtained as a colorless powder (454 mg, 57%): mp229-230° C.; ¹ H NMR (DMSO-d₆) 1.27-1.90 (m, 6H), 2.75-3.80 (m, 7H),4.22-4.41 (m, 2H), 6.71 (d, J=7.2 Hz, 2H), 8.82 (d, J=9.0 Hz, 2H),7.21-7.42 (m, 4H), 9.12 (s, 1H), 10.96 and 11.15 (overlapping bs, 1H);Anal. Calcd for C₂₀ H₂₅ Cl₂ NO₂ : C, 62.83; H, 6.59; N, 3.66. Found: C,62.75; H, 6.59; N, 3.52.

EXAMPLE 26 2-Benzyl-1-(2-(4-hydroxyphenoxy)ethyl)piperidineHydrochloride ##STR49##

From a mixture of 2-benzylpiperidine hydrochloride (500 mg, 2.36 mmol),2-(4-hydroxyphenoxy)ethyl bromide (614 mg, 2.83 mmol) and NaHCO₃ (407mg, 4.84 mmol) in CH₃ CN (20 mL) was obtained the free base of the titlecompound as a brown oil (467 mg, 64%): ¹ H NMR (CDCl₃) 1.20-1.70 (m, 6H), 2.50-2.61 (m, 2 H), 2.69-2.80 (m, 1 H), 2.93-3.06 (m, 2 H),3.12-3.24 (m, 2 H), 3.99-4.13 (m, 2 H), 6.74 (s, 4 H), 7.14-7.31 (m, 5H).

The hydrochloride was obtained as a colorless solid: mp 215-216° C.; ¹ HNMR (CD₃ OD) 1.40-2.07 (m, 6 H), 2.70-4.43 (m, 9 H), 6.72-6.79 (m, 2 H),6.85-6.92 (m, 2 H), 7.24-7.39 (m, 5 H); Anal. Calcd for C₂₀ H₂₆ ClNO₂ :C, 69.04; H, 7.53; N, 4.03. Found: C, 69.02; H, 7.30, N, 3.95.

EXAMPLE 27 2-Benzyl-1-(3-(4-hydroxyphenoxy)propyl)piperidineHydrochloride ##STR50##

From a mixture of 2-benzylpyridine hydrochloride (500 mg, 2.36 mmol),3-(4-hydroxyphenoxy)propyl bromide (654 mg, 2.83 mmol), and NaHCO₃ (407mg, 4.84 mmol) in CH₃ CN (20 mL) was obtained the free base of the titlecompound as a yellow oil (385 mg, 45%): ¹ H NMR (CDCl₃) 1.20-1.70 (m, 6H), 1.93-2.04 (m, 2 H), 2.36-3.16 (m, 7 H), 3.90-3.98 (t, 2 H. J=6.15Hz), 6.70-6.80 (m, 4 H), 7.12-7.30 (m, 5 H).

The hydrochloride was obtained as a light brown solid: mp 163-164° C.; ¹H NMR (DMSO) 1.25-1.90 (m, 5 H), 2.10-2.30 (m, 2 H), 2.70-3.18 (m, 3 H),3.20-3.62 (m, 5 H), 3.93-4.02 (m, 2 H), 6.64-6.84 (m, 4 H), 7.18-7.42(m, 5 H), 8.99 (s, 1 H), 10.53-10.80 (d, 1 H, J=39.3); Anal. Calcd forC₂₁ H₂₈ ClNO₂ : C, 69.69; H, 7.80; N, 3.87. Found: C, 69.70; H, 7.67; N,3.83.

EXAMPLE 28 2-Benzyl-1-(4-(4-hydroxyphenoxy)butyl)piperidineHydrochloride ##STR51##

A)4-(4-Benzyloxyphenoxy)butyl bromide. From a mixture of4-(benzyloxy)phenol (11.7 g, 58.4 mmol), 1,4-dibromobutane (35.0 mL,63.3 g, 293 mmol) and K₂ CO₃ (8.07 g, 58.4 mmol) in CH₃ CN (200 mL) wasobtained the title compound as a tan solid (10.8 g, 55%): ¹ H NMR(CDCl₃) 1.86-1.98 (m, 2 H), 2.00-2.13 (m, 2 H), 3.44-3.53 (t, 2 H, J=6.6Hz), 3.90-3.99 (t, 2 H, J=6.0 Hz), 5.02 (s, 2 H), 6.77-6.85 (m, 2 H),6.85-6.94 (m, 2 H), 7.27-7.46 (m, 5 H).

B) 2-Benzyl-1-(4-(4-benzyloxyphenoxy)butyl)piperidine. From a mixture of2-benzylpiperidine hydrochloride (1.00 g, 4.72 mmol),4-(4-benzyloxyphenoxy)butyl bromide (1.90 g, 5.66 mmol), and NaHCO₃(80.0 mg, 9.44 mmol) in CH₃ CN (50 mL) was obtained the title compoundas a yellow solid (428 mg, 21%), ¹ H NMR (CDCl₃) 1.22-2.42 (m, 9 H),3.03-3.68 (m, 8 H), 3.89-4.02 (m, 2 H), 5.01 (s, 2 H), 6.74-6.94 (m, 4H), 7.12-7.45 (m, 10 H).

C) 2-Benzyl-1-(4-(4-hydroxyphenoxy)butyl)piperidine hydrochloride. Amixture of 2-benzyl-1-(4-(4-benzyloxyphenoxy)butyl)piperidine (400 mg,0.93 mmol) and Pd (40.0 mg, 10% on carbon) in MeOH (20 mL) washydrogenated (40 psi) for 24 hours. The catalyst was removed byfiltration and the solvent was removed from the filtrate to give ayellow oil. The oil was purified on silica gel (1.5×40 cm) with 10% EtOHin CHCl₃ elution to yeild the free base of the title compound as a pinkoil (313 mg): ¹ H NMR (CDCl₃) 1.20-1.98 (m, 10 H), 2.62-3.29 (m, 7 H),3.75-3.85 (t, 2 H, J=6.0 Hz), 6.63-6.72 (d, 2 H, J=8.7 Hz), 6.76-6.85(d, 2 H, J=8.7 Hz), 7.12-7.33 (m, 5 H).

The hydrochloride was obtained as a colorless solid (185 mg, 53%): mp161-162° C.; ¹ H NMR (DMSO-d₆) 1.28-1.94 (m, 10 H), 2.96-3.62 (m, 7 H),3.90 (s, 2 H), 6.63-6.71 (d, 2 H, J=9.0 Hz), 6.71-6.79 (d, 2 H, J=8.7Hz), 7.20-7.38 (m, 5 H), 8.95 (s, 1 H), 10.28-10.55 (m, 1 H).

EXAMPLE 29 1-[2-(4-amino-3-nitrophenoxy)ethyl]-2-benzylpiperidine##STR52##

From a mixture of 2-benzyl-piperidine (1.08 mg, 6.16 mmol),(4-amino-3-nitrophenoxy)ethyl bromide (796 mg, 3.05 mmol) and NaI (100mg) in toluene (25 mL) was obtained 738 mg (68%) of the title compoundas a yellow powder, mp 174-6° C. ¹ H NMR (CDCl₃): 1.23-1.29 (m, 2H),1.48-1.66 (m, 4H), 2.48-2.58 (m, 2H), 2.66-2.72 (m.1H), 2.93-3.02 (m,2H), 3.11-3.20 (m, 2H), 4.06-4.10 (m, 2H), 6.759 (d, 1H, J=9), 7.092(dd, 1H, J=9; 3), 7.16-7.30 (m, 5H), 7.959 (d, 1H, J=3).

EXAMPLE 30 2-Benzyl-1-(4-(2-oxobenzimidazol-5-oxy) ethyl)piperidine##STR53##

a) A mixture of of1-[2-(4-amino-3-nitrophenoxy)ethyl]-2-benzylpiperidine (705 mg, 1.99mmol) and Raney Ni (about 200 mg) in EtOH (15 mL) was shaken under H₂(35-25 parr) for 4 h, then filtered. The filtrate was evapoated, and theresidure was purified by chromatography over silica gel (CHCl₃ --MeOH,3:2) to give 2-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (650 mg,98%) as a brown viscous oil. ¹ H NMR (CDCl₃): 1.22-1.32 (m, 2H),1.49-1.52 (m, 3H), 2.49-2.56 (m, 2H), 2.756 (bs, 2H, NH₂), 2.96-3.06 (m,2H), 3.13-3.24 (m, 2H), 3.520 (bs, 2H, NH2), 4.02-4.12 (m, 2H), 6.285(dd, 1H, J=9; 3), 6.350 (d, 1H, J=3), 6.640 (d, 1H, J=9), 7.16-7.30 (m,5H).

b) A mixture of 2-benzyl-1-[(3,4-diaminophenoxy)ethyl]piperidine (650mg, 2.0 mmol) and CDI (390 mg, 2.4 mmol) in toluene (25 mL) was refluxedfor 24 h, then cooled to r.t. The mixture was evaporated, and theresidue was purified by chromatography over silica gel (CHCl₃ --MeOH,3:2) to give 422 mg (60%) of the title compound as a viscous oil. Thehydrochloride is highly hygroscopic. ¹ H NMR (DMSO-d₆): 10.486 (s, 1H,NH), 10.650 (s, 1H, NH).

The data for the compounds of Examples 3, 4, 5, 6, 7, 8, 17, 18, 20, 21,22, 24, 25, 26, 27, 28 and 30 described above in the expressed clonedNMDA subtypes is shown below in Table 1 along with maximal electroshock(MES) data for several compounds:

                  TABLE 1                                                         ______________________________________                                        Subunits (IC.sub.50 (μM))                                                                            MES (ED.sub.50)                                     Compound                                                                              1A/2A    1A/2B   1A/2C  1A/2D (mg/kg)                                 ______________________________________                                        Example 8                                                                             3        8        45          4                                       Example 7                                                                             4        12       45          2.5                                     Example 5                                                                             5        8        55          4                                       Example 4                                                                             8        15      125                                                  Example 17                                                                            13       35      110    >300  1                                       Example 2                                                                             15       19       33                                                  Example 6                                                                             17       25      130                                                  Example 18                                                                            23       50      >100   >300                                          Example 20                                                                            14       22       70                                                  Example 21                                                                            60       35      240                                                  Example 22                                                                            80       6       180                                                  Example 24                                                                            55       22      160                                                  Example 25                                                                            62       4.2     160                                                  Example 26                                                                            80       15      150                                                  Example 27                                                                            30       16       40                                                  Example 28                                                                            15       10      110                                                  Example 30                                                                            7.5      5        33                                                  ______________________________________                                    

The data shows that the 2-substituted piperidine analogs of thisinvention exhibit selectivity for 2A and 2B subtype receptors comparedto 2C and 2D subtype receptors. Certain 2-substituted piperidine analogsalso have in vivo activity as an anticonvulsant in MES experiments inmice.

What is claimed is:
 1. A compound represented by the formula: ##STR54##or a pharmaceutically acceptable salt thereof wherein Ar¹ is amonocyclic heteroaryl group, which may be independently substituted byhydrogen, hydroxy, alkyl, a halogenated alkyl group, halogen, nitro,aryl, aralkyl, amino, a lower alkyl amino group or a lower alkoxygroup;Ar² is independently aryl or a heteroaryl group, which may beindependently substituted by hydrogen, hydroxy, alkyl, a halogenatedalkyl group, halogen, nitro, aryl, aralkyl, or a lower alkoxy group;each R¹ is independently hydrogen, alkyl or hydroxy; each R² isindependently hydrogen, alkyl or hydroxy; Z is --CH₂ --, O, S or NR³ ; mis 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5;with the proviso that when Zis CH₂, m is 0, n is 3, and R² is hydroxy, Ar² is not halogensubstituted aryl.
 2. A pharmaceutical composition useful for treatingdisorders responsive to the selective blockade of N-methyl-D-aspartatereceptor subtypes which disorders are selected from stroke, cerebralischemia, central nervous system trauma, hypoglycemia, neurodegenerativedisorders, anxiety, convulsions, aminoglycoside antibiotics-inducedhearing loss, migraine headaches, chronic pain, psychosis, glaucoma, CMVretinitis, urinary incontinence, or opioid tolerance or withdrawal, saidcomposition comprising a pharmaceutically acceptable carrier or diluentand a therapeutically acceptable carrier or diluent and anN-methyl-D-aspartate receptor antagonist effective amount of at leastone compound of claim
 1. 3. A method for treating disorders responsiveto the selective blockade of N-methyl-D-aspartate receptor subtypes inan animal suffering therefrom which comprises administering anN-methyl-D-aspartate receptor antagonist effective amount of at leastone compound represented by the formula: ##STR55## or a pharmaceuticallyacceptable salt thereof wherein Ar¹ is a monocyclic heteroaryl group,which may be independently substituted by hydrogen, hydroxy, alkyl, ahalogenated alkyl group, halogen, nitro, aryl, aralkyl, amino, a loweralkyl amino group or a lower alkoxy group;Ar² is independently aryl or aheteroaryl group, which may be independently substituted by hydrogen,hydroxy, alkyl, a halogenated alkyl group, halogen, nitro, aryl,aralkyl, or a lower alkoxy group; each R¹ is independently hydrogen,alkyl or hydroxy; each R² is independently hydrogen, alkyl or hydroxy; Zis --CH₂ --, O, S or NR³ ; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5.4. The method according to claim 3, wherein said disorder is stroke,cerebral ischemia, central nervous system trauma or hypoglycemia.
 5. Themethod according to claim 3, wherein said disorder is aneurodegenerative disorder.
 6. The method according to claim 3, whereinsaid disorder is Parkinson's disease.
 7. The method according to claim3, wherein said disorder is anxiety, convulsions or chronic pain.
 8. Themethod according to claim 3, wherein said disorder is migraine headache.9. The method according to claim 3, wherein said disorder is glaucomaand CMV retinitis.
 10. The method according to claim 3, wherein saiddisorder is psychosis.
 11. The method according to claim 3, wherein saiddisorder is urinary incontinence.
 12. The method according to claim 3,wherein said disorder is opioid tolerance or withdrawal.
 13. The methodaccording to claim 3, wherein said disorder is amioglycosideantibiotics-induced hearing loss.